Neuroprotective strategies in parkinson’s disease: protection against progressive nigral damage induced by free radicals

Brain undergoes neurodegeneration when excess free radicals overwhelm antioxidative defense systems during senescence, head trauma and/or neurotoxic insults. A site-specific accumulation of ferrous citrate-iron complexes in the substantia nigra dopaminergic neurons could lead to exaggerated dopamine turnover, dopamine auto-oxidation, free radical generation, and oxidant stress. Eventually, this iron-catalyzed dopamine auto-oxidation results in the accumulation of neuromelanin, a progressive loss of nigral neurons, and the development of Parkinson's disease when brain dopamine depletion is greater than 80%. Emerging evidence indicates that free radicals such as hydroxyl radicals ((.-)OH) and nitric oxide ((.-)NO) may play opposite role in cell and animal models of parkinsonism. (.-)OH is a cytotoxic oxidant whereas oNO is an atypical neuroprotective antioxidant. (.-)NO and S-nitrosoglutathione (GSNO) protect nigral neurons against oxidative stress caused by 1-methyl-4-phenylpyridinium (MPP(+)), dopamine, ferrous citrate, hemoglobin, sodium nitroprusside and peroxynitrite. MPP(+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), increases the nigral uptake of iron complexes and dopamine overflow leading to the generation of (.-)OH, protein oxidation, lipid peroxidation, and associated retrograde degeneration. In addition to GSNO, MPP(+)-induced oxidative neurotoxicity can be prevented by antioxidants including selegiline, 7-nitroindazole, 17beta-estradiol, melatonin, alpha-phenyl-tert-butylnitrone and U78517F. Similar to selegiline, 7-nitroindazole is a MAO-B inhibitor, which blocks the bio-activation of MPTP and oxidative stress. Freshly prepared but not light exposed, (.-)NO-exhausted GSNO is about 100 times more potent than the classic antioxidant glutathione. Via S-nitrosylation, GSNO also inhibits proteolysis and cytotoxicity caused by caspases and HIV-1 protease. Furthermore, in addition to protection against serum deprivation stress, the induction of neuronal NOS1 in human cells increases tolerance to MPP(+)-induced neuro-toxicity since newly synthesized (.-)NO prevents apoptosis possibly through up-regulation of bcl-2 and down regulation of p66(shc). In conclusion, reactive oxygen species are unavoidable by-products of iron-catalyzed dopamine auto-oxidation, which can initiate lipid peroxidation, protein oxidation, DNA damage, and nigral loss, all of which can be prevented by endogenous and exogenous (.-)NO. Natural and man-made antioxidants can be employed as part of preventative or neuroprotective treatments in Parkinson's disease and perhaps dementia complexes as well. For achieving neuroprotection and neuro-rescue in early clinical parkinsonian stages, a cocktail therapy of multiple neuroprotective agents may be more effective than the current treatment with extremely high doses of a single antioxidative agent.     

Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.     

Feasibility study for measuring patients’ visual acuity at home by their caregivers

Purpose:To assess the feasibility of measuring patients’ visual acuity (VA) in their homes by their caregivers.Methods:Patients consulting in a tertiary eye care institute were prospectively enrolled with informed consent. All underwent standard COMPlog distance VA testing. Patients and caregivers were oriented to test distance VA using the Peek Acuity app. The app was installed on the caregiver’s or patient’s smartphone. The patient’s VA was measured by the caregiver in the clinic (baseline value) under supervision. After 1 week, the caregivers recorded the patient’s VA with the Peek Acuity app at their home and reported the value in a telephone consultation. A questionnaire to assess the ease of using the app was administered at both the baseline visit and 1 week later.Results:A total of 100 patients (age group: 13 to 76 years) and 100 caregivers (age group: 17 to 65 years) participated. VA measurements with the Peek Acuity app were comparable with COMPlog (P > 0.1) both during the baseline and after 1-week measurement, regardless of the underlying ocular condition or educational level of the caregivers/patients. Most caregivers (95%) felt the app was easy to use.Conclusion:Though the Peek Acuity app was originally developed for health care workers to be used in field visits, we found that with proper orientation, the layperson can also use it. Such orientation can enable caregivers to effectively measure VA at home. Such a tool would enhance teleophthalmology consultations and can minimize the need for short follow-up visits.     

Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease

JUSTIFICATION: Acute rheumatic fever and rheumatic chronic valvular heart disease is an important preventable cause of morbidity and mortality in suburban and rural India. Its diagnosis is based on clinical criteria. These criteria need verification and revision in the Indian context. Furthermore, there are glaring differences in management protocols available in literature. These facts prompted Indian Academy of Pediatrics to review the management of rheumatic fever. PROCESS: Management of Rheumatic fever was reviewed and recommendation was formulated at national consultative meeting on 20th May 2007 at New Delhi. OBJECTIVES: To formulate uniform guidelines on management of acute rheumatic fever and rheumatic heart disease in the Indian context. Guidelines were formulated for the management of streptococcal pharyngitis, acute rheumatic fever and its cardiac complication as well as secondary prophylaxis for recurrent episodes. RECOMMENDATIONS: (1) Streptococcal eradication with appropriate antibiotics (Benzathine penicillin single dose or penicillin V oral or azithromycin). (2) Diagnosis of rheumatic fever based on Jones criteria. (3) Control inflammatory process with aspirin with or without steroids (total duration of treatment of 12 weeks). (4) Treatment of chorea according to severity (therapy to continue for 2-3 weeks after clinical improvement). (5) Protocol for managing cardiac complication like valvular heart disease, congestive heart failure and atrial fibrillation. (6) Secondary prophylaxis with benzathine penicillin and management of anaphylaxis.     

A Hybrid Markov Chain–von Mises Density Model for the Drug-Dosing Interval and Drug Holiday Distributions

Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9713-5) contains supplementary material, which is available to authorized users.KEY WORDS: adherence, circular distribution, compliance, dosing patterns, runs     

Multiple bladder calculi: a rare cause of irreducible uterine prolapse

Background A vesical calculus in a prolapsed cystocele is rare. Objective To highlight bladder calculi as a cause of irreducible uterine prolapse. Case Report A case of irreducible total uterine prolapse caused by multiple vesical calculi is presented. Bladder stones were removed through vaginal cystolithotomy followed by vaginal hysterectomy. Conclusion In cases of acute irreducible pelvic organ prolapse, the possibility of bladder stones should be kept in mind and X-ray pelvis including the prolapsed mass should be done to confirm the diagnosis.     

Numerical Simulation on Thermal Stresses and Solidification Microstructure for Making Fiber-Reinforced Aluminum Matrix Composites

The fabrication of fiber-reinforced metal matrix composites (MMCs) mainly consists of two stages: infiltration and solidification, which have a significant influence on the properties of MMCs. The present study is primarily focused on the simulation of the solidification process and the effect of the active cooling of fibers with and without nickel coating for making the continuous carbon fiber-reinforced aluminum matrix composites. The thermomechanical finite element model was established to investigate the effects of different cooling conditions on the temperature profile and thermal stress distributions based on the simplified physical model. The predicted results of the temperature distribution agree well with the results of the references. Additionally, a three-dimensional cellular automata (CA) finite element (FE) model is used to simulate the microstructure evolution of the solidification process by using ProCAST software. The results show that adding a nickel coating can make the heat flux smaller in the melt, which is favorable for preventing debonding at the coating/fiber and alloy interface and obtaining a finer microstructure. In the presence of the nickel coating, the number of grains increases significantly, and the average grain size decreases, which can improve the properties of the resultant composite materials. Meanwhile, the predicting results also show that the interfaces of fiber–coating, fiber–melt, and coating–melt experience higher temperature gradients and thermal stresses. These results will lead to the phenomenon of stress concentration and interface failure. Thus, it was demonstrated that these simulation methods could be helpful for studying the solidification of fiber-reinforced MMCs and reducing the number of trial-and-error experiments.